1. Field of the Invention
The invention relates to an improved process for the preparation of duloxetine, duloxetine intermediates, and duloxetine hydrochloride.
2. Discussion of the Related Art
Duloxetine hydrochloride (Compound I) is the international commonly accepted name for N-methyl-N-[(3S)-(3-(1-naphthyloxy)-3-thien-2-yl)propyl]amine hydrochloride (which is also known as methyl-[(S)-3-(naphthalen-1-yloxy)-3-thiophen-2-yl-propyl]-amine) hydrochloride and has an empirical formula of C18H19NOS.HCl and a molecular weight of 333.88. Duloxetine hydrochloride is a commercially marketed pharmaceutically active substance known to be useful for the treatment of major depressive disorder.

Duloxetine hydrochloride is a selective serotonin and norepinephrine reuptake inhibitor (SSNRI) for oral administration. In the United States, duloxetine hydrochloride is marketed under the name Cymbalta® for the treatment of major depressive disorder and diabetic peripheral neuropathic pain. In Europe, duloxetine hydrochloride has been approved for the treatment of major depressive disorder and also for the treatment of moderate to severe stress urinary incontinence.
Duloxetine and its pharmaceutically acceptable salts are disclosed in U.S. Pat. No. 5,023,269 (“the '269 patent”). No examples related to the preparation of (S)-duloxetine, or one of its pharmaceutically acceptable salts (e.g., the hydrochloride salt), are disclosed. In the '269 patent, racemic duloxetine was prepared by demethylating the corresponding N,N-dimethylpropanamine derivative using phenyl chloroformate to yield the corresponding carbamate as an intermediate. The carbamate was then hydrolyzed to afford racemic duloxetine as an oil, and was subsequently isolated as the oxalate salt. The process disclosed in the '269 patent for obtaining racemic duloxetine is shown in Scheme 1.

(S)-Duloxetine can be obtained using the same strategy outlined in Scheme 1, but starting from (S)-3-dimethylamino-1-(2-thienyl)-1-propanol (Compound S-II), as described in Tetrahedron Letters, 31, (49), 7101-04 (1990) and in U.S. Pat. No. 5,362,886 (“the '886 patent”). The '886 patent also provides a procedure for the preparation of (S)-duloxetine in the form of its hydrochloride salt.

Other references related to the preparation of duloxetine hydrochloride from compound of formula S-II are WO 04/056795, WO 03/062219 and WO 00/61540.
There are several other known methods for producing duloxetine and its salts. Generally, these alternative processes include resolution of a key intermediate or a stereoselective synthesis usually involving a stereospecific reduction of a keto group to give the corresponding alcohol. These other processes include those disclosed in: WO 03/070720; WO 04/011452; WO 04/024708; T. Chirality, 12:26-29 (2000); Advanced Synthesis and Catalysis (2003), 345(1+2), 261-274; WO 04/005307; JP 2004123596; WO 04/13123; WO 04/005220; and Tetrahedron: Asymmetry (2003), 14(12), 1631-1636.
In patent application WO 04/056795 duloxetine hydrochloride is prepared by using a phase transfer catalyst for the reaction of (S)-3-(dimethylamino)-1-(2-thienyl)-1-propanol (Compound S-II) and 1-fluoronaphthalene (Scheme I, Compound III) with sodium hydroxide in DMSO.